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学科主题: 药学
题名:
Intratumoral estrogen sulfotransferase induction contributes to the anti-breast cancer effects of the dithiocarbamate derivative TM208
作者: Ji, Xi-wei1,2; Chen, Guang-ping4; Song, Yan5; Hua, Ming1; Wang, Li-jie1; Li, Liang1; Yuan, Yin1; Wang, Si-yuan1; Zhou, Tian-yan1,3; Lu, Wei1,3
关键词: breast cancer ; dithiocarbamate ; tamoxifen ; estrogen ; estrogen sulfotransferase ; human tumor xenograft model ; uterotropic bioassay
刊名: ACTA PHARMACOLOGICA SINICA
发表日期: 2015-10-01
DOI: 10.1038/aps.2015.14
卷: 36, 期:10, 页:1246-1255
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Chemistry, Multidisciplinary ; Pharmacology & Pharmacy
研究领域[WOS]: Chemistry ; Pharmacology & Pharmacy
关键词[WOS]: STEROID-PRODUCING ENZYMES ; CYTOSOLIC SULFOTRANSFERASES ; AROMATASE ACTIVITIES ; SEX STEROIDS ; IN-SITU ; EXPRESSION ; TAMOXIFEN ; CELLS ; LIVER ; CARCINOMA
英文摘要:

Aim: Sulfotransferase-catalyzed sulfation is the most important pathway for inactivating estrogens. Thus, activation of estrogen sulfotransferase (EST) may be an alternative approach for the treatment of estrogen-dependent breast cancer. In this study we investigated the involvement of EST in anti-breast cancer effects of the dithiocarbamate derivative TM208 in vitro and in vivo.

Methods: The viability of human breast cancer MCF-7 cells was determined using a SBB assay. Nude mice bearing MCF-7 cells were orally administered TM208 (50 and 150 mg.kg(-1).d(-1)) for 18 days. The xenograft tumors and uteri were collected. The mRNA expression of EST was examined with real-time PCR. EST protein was detected with Western blot, ELISA or immunohistochemical staining assays. A radioactive assay was used to measure the EST activity. Uterotropic bioassay was used to examine the uterine estrogen responses.

Results: Treatment with TM208 (10, 15 and 20 mu mol/L) concentration-dependently increased EST expression in MCF-7 cells in vitro. Co-treatment with triclosan, an inhibitor of sulfonation, abolished TM208-induced cytotoxicity in MCF-7 cells. TM208 exhibited an apparent anti-estrogenic property: it exerted more potent cytotoxicity in E2-treated MCF-7 cells. In the nude mice bearing MCF-7 cells, TM208 administration time-dependently increased the expression and activity of EST, and blocked the gradual increase of E2 concentration in the xenograft tumors. Furthermore, TM208 administration blocked the estrogens-stimulated uterine enlargement. Tamoxifen, a positive control drug, produced similar effects on the expression and activity of EST in vitro and in vivo.

Conclusion: The induction of EST and reduction of estrogen concentration contribute to the anti-breast cancer action of TM208 and tamoxifen. TM208 may be developed as anticancer drug for the treatment of estrogen receptor-positive breast cancer.

语种: 英语
所属项目编号: 81273583
项目资助者: National Natural Science Foundation of China (NSFC)
WOS记录号: WOS:000362459200011
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/61444
Appears in Collections:北京大学药学院_药剂学系_期刊论文

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作者单位: 1.Peking Univ, Sch Pharmaceut Sci, Dept Pharmaceut, Beijing 100191, Peoples R China
2.Peking Univ, Hosp 1, Inst Clin Pharmacol, Beijing 100191, Peoples R China
3.Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
4.Oklahoma State Univ, Ctr Vet Hlth Sci, Dept Physiol Sci, Stillwater, OK 74078 USA
5.Peking Univ, Sch Pharmaceut Sci, Dept Mol & Cellular Pharmacol, Beijing 100191, Peoples R China

Recommended Citation:
Ji, Xi-wei,Chen, Guang-ping,Song, Yan,et al. Intratumoral estrogen sulfotransferase induction contributes to the anti-breast cancer effects of the dithiocarbamate derivative TM208[J]. ACTA PHARMACOLOGICA SINICA,2015,36(10):1246-1255.
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